Development and Scale-Up of a Crystallization ... - ACS Publications

Subscriber access provided by Kent State University Libraries

Full Paper

Development and scale-up of a crystallization process to improve an API’s physiochemical and bulk powder properties Landon Durak, Miriam Kennedy, Marianne Langston, Christopher Mitchell, Gary Morris, Michael E. Perlman, Kaitlyn Wendl, Frederick Hicks, and Charles Dimitrios Papageorgiou Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00344 • Publication Date (Web): 10 Jan 2018 Downloaded from http://pubs.acs.org on January 10, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Organic Process Research & Development is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Organic Process Research & Development

Development and scale-up of a crystallization process to improve an API’s physiochemical and bulk powder properties Landon Durak1, Miriam Kennedy2, Marianne Langston3, Christopher Mitchell1, Gary Morris2, Michael Perlman3, Kaitlyn Wendl3, Frederick Hicks1 and Charles D. Papageorgiou*1 1 Takeda Pharmaceuticals International Co., Process Chemistry, 40 Landsdowne St., Cambridge, MA, 02139 2 APC Ltd, Building 11, Cherrywood Business Park, Loughlinstown, Dublin, Ireland 3 Takeda Pharmaceuticals International Co., Pharmaceutics Research-Analytical Development, 40 Landsdowne St., Cambridge, MA, 02139

1 ACS Paragon Plus Environment

Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 28

Table of Contents Graphic


Page 3 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Keywords: thermalcycling, particle engineering, crystallization, powder properties, scale-up

Abstract A revised crystallization process for TAK-117, a selective PI3Kα inhibitor currently in Phase 1b clinical trials, was developed that greatly improved the overall purity, recovery, and physiochemical and bulk powder properties of the isolated product. The original process afforded material that was prone to agglomeration during drying resulting in significant product losses during sieving as well as issues with drug product (DP) manufacturability. Opportunities to explore a wide array of possible crystallization routes and solvent options were limited by TAK-117 being only sparingly soluble in most commonly used organic solvents apart from DMSO and acidic systems. However, reasonable productivities were achieved using DMSO at elevated temperatures (100 °C) and the optimized process leveraged thermalcycling to improve the aspect ratio of the isolated crystals, minimize agglomeration during drying, and improve the powder’s bulk properties. The revised process was found to produce material of acceptable quality across a total of 6 batches at 15 and 30 kg scales.



Page 4 of 28

Introduction Crystallization is an important unit operation for the separation and purification of solid-state compounds, and one that is routinely adopted within the pharmaceutical industry.1 Multistep batch synthetic routes for drug substances typically contain several solid-state isolation points including the crystallization of intermediate compounds as well as the final active pharmaceutical ingredient (API). In addition to crystal purity and yield, it is equally important to control the crystal form2-4, morphology5, shape and size6, 7, and hence the particle size distribution (PSD), all of which define the API’s physiochemical and bulk powder properties8, 9 that can impact a compound’s solubility as well as the drug product’s bioavailability and/or manufacturability. While a crystallization process is being developed, there are multiple strategies for the optimization of the aforementioned product attributes.10, 11 Process development usually begins with selection of an appropriate solvent system and crystallization mode (e.g. reactive, antisolvent, evaporative or cooling) to deliver high yield, purity and appropriate form control.12, 13 Crystal size and morphology are most typically optimized once the solvent system is selected, as the range of process parameters available to tailor the product’s powder properties are numerous (e.g. addition and cooling rates, seed size, mass and process addition point), all of which can have a significant impact. When the control of these parameters is found to be limiting, alternative crystallization technologies can be adopted such as wetmilling, thermalcycling and continuous processing.14‒17

Figure 1. Final steps of the TAK-117 manufacturing process TAK-117 is a selective PI3Kα inhibitor currently in Phase 1b clinical trials whose manufacturing process relies on a palladium (Pd)-catalyzed Suzuki coupling reaction as the last bond-forming step. As a result, a discreet purification process is required to control the Pd levels within International Conference on Harmonisation (ICH) guidelines (Figure 1).18 During the original manufacturing


Page 5 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


process developed by discovery chemistry and used to support the Investigational New Drug (IND)enabling toxicological studies as well as first in human clinical trials, the poorly soluble crude TAK117 was dissolved in acidified methanol at 45 °C. This solution was then slurried with 100 wt% activated carbon, filtered through Celite® and the carbon washed with hot methanol. The filtrate was then subjected to two further treatments with decreasing quantities of activated carbon and SiliCycle® SiliaMetS Thiol scavenger (20 wt% each then 10 wt% each). The solids were washed with hot methanol and the filtrate was polish filtered before being concentrated under vacuum. The resulting solution was cooled to 10 ‒ 15 °C and 1.0 eq. of ammonium hydroxide (NH4OH) was added to precipitate the product. The slurry was filtered, washed with water and methanol and finally dried under vacuum at 50 °C. This process was very effective in removing residual Pd, but resulted in significant loss of material, either on the carbon or as a result of product precipitation during the various filtration steps. Furthermore low stability of TAK-117 under acidic conditions at elevated temperatures was a concern. Finally, the isolated product had a very small particle size and was highly agglomerated (Table 2), exhibiting undesirable bulk powder properties for downstream drug product (DP) manufacturing. Two 5 kg batches were manufactured using the above process, affording TAK-117 in 56 and 69 % yield, 97.5 liquid chromatography area percent (LCAP) purity and with 9 ‒ 14 ppm Pd. Clearly this process was extremely laborious and was not deemed suitable for further scale-up. A revised, more efficient process was therefore needed that would afford better control of particle size and morphology. Examination of the solubility of TAK-117 across a range of commonly used organic solvents revealed that it was sparingly soluble in all solvents other than acidic systems and exhibited modest solubility in dimethyl sulfoxide (DMSO) at elevated temperatures (Table 1). This paper describes the subsequent studies conducted toward developing and scaling up into the pilot plant a revised crystallization process that maximized product recovery and HPLC purity, improved the API’s physiochemical properties as well as controlled its bulk properties. Table 1. HPLC-measured solubility of TAK-117 in a range of solvents at 20 and 50 °C.



Solvent

Solubility at 20 °C [mg/mL]

Page 6 of 28

Solubility at 50 °C [mg/mL]

DMSO

5.33

11.22

DMF

1.49

2.27

NMP

8.16

9.07

Methanol

0.17

0.34

1,4-Dioxane

0.16

0.44

DME

0.07

0.26

Water

N/D1

N/D

Toluene

N/D

N/D

THF

0.12

0.40

Methylene chloride

N/D

0.02

Acetonitrile

0.01

0.02

Formic acid (10 % v/v)

16.9

N/A2


43.5

N/A


91.0

N/A


166.4

N/A


250.6

N/A

1. not detected; 2. not available Experimental Section General experimental procedures. Formic acid recrystallization process. TAK-117 (20 g, 0.055 moles, 1 eq.) was dissolved in 40 % v/v aqueous formic acid (400 mL, 20 vol.) at 20 °C in a 1L Mettler Toledo OptiMax vessel equipped with a 45° pitched-blade impeller (4-blade, 45 mm diameter). Stirring was initiated at 408 rpm and 25 % w/v aqueous sodium hydroxide (NaOH) was added in two portions. The first portion (174 mL, 8.65 vol.) was added over 0.5 h via an OptiMax dosing unit, while the second (174 mL, 8.65 vol.) was added over 8.2 h to a pH endpoint of 3.6. The resulting suspension was held for 1 h after which time it was filtered, reslurried twice with deionised water (2 x 100 mL, 2 x 10 vol.) and dried in a vacuum oven at 40 °C to constant weight to afford TAK-117 as an off-white solid in 98.8 % yield. 1st Generation DMSO process. TAK-117, crude (15.04 kg, 41.4 moles, 1.0 eq.) and SiliaMetS® Diamine (12.10 kg, 80 wt%.) were charged to a 1,000 L stainless steel reactor equipped with a 6 ACS Paragon Plus Environment

Page 7 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Pfaudler impeller followed by DMSO (453 kg, 27.3 vol.). Stirring was initiated at 80 rpm. Activated carbon (Darco™ G-60, 3.02 kg, 20 wt%) and Celite® (3.4 kg, 23 wt%) were both charged as suspensions in DMSO (15.1 kg, 0.9 vol. and 30.2 kg, 1.8 vol. respectively) to minimize dust generation. The resulting slurry was heated to 95 °C over 3 h and held at this temperature for a total of 4.5 h before being filtered into a clean, dry 1,600 L glass lined reactor for the final isolation. The carbon containing wet cake was washed twice with hot (~95 °C) DMSO (33.2 kg, 2.0 vol.) and the resulting solution was cooled to 70 °C over 1.5 h. Water (90.6 L, 6.0 vol.) was dosed over 3.5 h and the agitation speed was reduced to 70 rpm. The suspension was cooled to 20 °C over 10 h and aged at this temperature for 1.5 h after which time in-process analysis showed that the concentration of the product in the mother liquor was below the specification of not more than (NMT) 0.23 % w/w (0.14 % w/w). The product was therefore filtered using a 0.4 m2 Rosenmund® agitated filter dryer (AFD). The wet cake was washed with a 10:1 v/v mixture of DMSO:water (45.3 kg, 2.75 vol.) and then twice with water (37.8 kg, 2 x 2.5 vol.) before being resuspended in water (227 kg, 15 vol.) and agitated at 26 rpm for 10 min. The suspension was finally filtered and dried under vacuum at 50 °C to afford 13.8 kg of TAK-117 as an off-white solid in 91.7 % yield. 2nd Generation DMSO process. TAK-117, crude (18.54 kg, 51.0 moles, 1.0 eq.) and SiliaMetS® Diamine (14.90 kg, 80 wt%) were charged to a 1,000 L stainless steel reactor equipped with a Pfaudler impeller followed by DMSO (558 kg, 27.3 vol.). Stirring was initiated at 75 rpm. Activated carbon (Darco™ G-60, 3.72 kg, 20 wt%) and Celite® (4.19 kg, 23 wt%) were both charged as suspensions in DMSO (18.6 kg, 0.9 vol. and 37.2 kg, 1.8 vol. respectively) to minimize dust generation. The resulting slurry was heated to 97 °C over 3.5 h and held at this temperature for a total of 4.5 h before being filtered into a clean, dry 1,600 L glass lined reactor for the final isolation. The carbon containing wet cake was washed twice with hot (~95 °C) DMSO (40.0 kg, 2.0 vol.) and the resulting solution was cooled to 90 °C over 20 min. Micronized TAK-117 (0.186 kg, 0.01 eq.) was suspended in DMSO (5.4 kg, 0.27 vol.) and charged to the reactor. The resulting seed bed was matured for 30 min before being cooled to 60 °C over 1.5 h and thermalcycled three times between 80 and 60 °C at a rate of 20 °C/h. After the third cycle the temperature was cooled to 25 °C over 5 h and



Page 8 of 28

water (112 kg, 6 vol.) was dosed over 6 h. In-process analysis showed that the concentration of the product in the mother liquor was below the specification of NMT 0.23 % w/w (0.20 % w/w). The product was therefore filtered using a 0.4 m2 Rosenmund® AFD. The wet cake was washed with a 10:1 v/v mixture of DMSO:water (81.8 kg, 4.0 vol.) and then twice with water (74.4 kg, 2 x 4.0 vol.) before being resuspended in ethanol (58.6 kg, 4 vol.) and agitated at 11 rpm for 22 min. The suspension was finally filtered, washed twice with n-heptane (51.1 kg, 2 x 4 vol.) and dried under vacuum at 50 °C to afford 16.2 kg of TAK-117 as an off-white solid in 87.2 % yield. Laser diffraction particle size method. A Malvern Mastersizer 2000 instrument equipped with a wet dispersion unit and Hydro Sight™ was used for all laser diffraction particle size analyses. Standard instrument settings were as follows: Mei evaluation mode, product refractive index setting of 1.52, dispersant refractive index of 1.33, dispersion unit speed of 2,500 rpm, water as the dispersant, sample measurement time of 10 s, 5 to 15 % obscuration limit, and 3 measurement cycles. The API was suspended in 1 % w/w Triton™ X-100 in water and then the sample was inverted approximately 30 times to mix. Samples were added dropwise to the wet dispersion unit containing water to give the desired obscuration, typically around 7 %. The average of the 3 measurements is reported. Dynamic imaging particle size and shape method. A QICPIC dynamic image analysis instrument (Sympatec, model R02) equipped with a LIQXI wet dispersion module with a flow cuvette fitted with a 0.2 mm thickness insert was used. The instrument settings were as follows: frame rate of 50 Hz, 120 sec measurement time, 120 rpm pump speed and stirrer speed of 200 rpm. The sample was suspended in 1% w/w Triton™ X-100 in water that was then inverted approximately 30 times to mix. Samples were added dropwise to 0.1% w/w Triton™ X-100 in water. The average of the 3 measurements is reported. The particle size distribution values reported are based on the Cylindrical Feret Volume equivalent diameter. The Cylindrical Feret Volume diameter represents the diameter of a sphere having the same volume as the cylinder constructed with Feret minimum as its base diameter and Feret maximum as its length.


Page 9 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


The aspect ratio was calculated by dividing the Feret minimum diameter by the Feret maximum diameter. The maximum and minimum Feret diameters are respectively the longest and shortest distance between two parallel lines that are tangent to the contour of the particle. A value of the aspect ratio of one identifies a perfect circle. As the value of the aspect ratio decreases, particle shape progressively deviates from circular and becomes needle-like. Historically the definition was the inverse of this (length/width) such that all values were equal to, or greater than 1.19 Differential scanning calorimetry.

A DSC Q200 or Q2000 instrument was used from TA

Instruments (New Castle, DE, USA) for all analyses performed. 1 to 2 mg of sample was sealed in an aluminum pan with a pinhole lid that was heated from 25 °C to 350 °C at 10 °C/minute, while the nitrogen sample purge was kept constant at 50 mL/min. Moisture sorption analysis. The moisture sorption was evaluated using a VTI SGA-100 Symmetric Vapor Sorption Analyzer or a VTI SGA-CX Symmetric Vapor Sorption Analyzer (TA Instruments). The sample (5 to 10 mg) was kept at a constant temperature of 25 °C while being exposed to various RH conditions. The adsorption-desorption isothermal cycle started at 0% RH. The RH increased to 95% RH, then decreased to 5% RH using 5% RH steps. The samples were allowed to equilibrate prior to stepping to the next RH condition using an equilibrium criterion of 0.001% weight change for 10 minutes, with a maximum equilibrium time of 120 minutes. Results and Discussion Precipitation from Aqueous Formic Acid TAK-117 exhibited good solubility and reasonable stability in both aqueous (40 % v/v) and acetonitrile (20 % v/v) formic acid solutions at 20 °C, with 99.6 LCAP purity, with 0.5 %, again consistent with greater crystallinity. Table 2. Comparison of the key TAK-117 solid-state properties from the original and 1st generation DMSO processes. Analysis XRPD

Original Process

1st Generation DMSO Process

Lower resolution and amorphous halo

Higher resolution without halo


Page 15 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


DSC

Melt onset at 295 °C

Melt onset at 307 ‒ 310 °C

GVS

1.6 % at 90 % RH (reversible)

0.5 % after 8 weeks at 60 °C (75 % RH) and 80 °C (desiccant). No form change.

No degradation or form change after 8 weeks at 60 °C (75 % RH) and 80 °C (desiccant).

(40x magnification)

Solid Stress

Batch analysis. A total of eight 15 kg batches were manufactured using the 1st generation TAK117/DMSO process, affording TAK-117 in 84-91 % yield and 98.95-99.83 LCAP purity. PSD analysis indicated variability in the laser diffraction particle size data as shown in Figure 4, with lots B and E affording larger particles. In addition, upon DP manufacture of batch A, it was found that a large amount of material (~20 %) was retained on the 2 mm screen used during blending.



Page 16 of 28

Figure 4. API product particle size (Malvern d50) and sieve data for batches manufactured via 1st and 2nd generation TAK-117/DMSO processes at scale (15 – 30 kg). Analysis of these particles under the microscope indicated the presence of agglomerates, which must have been generated during filtration and drying as they were absent at the end of the crystallization. Potential variability in the size and quantity of these >2 mm agglomerates could severely impact the DP manufacturability but was not captured by the developed laser diffraction-based PSD method.20-23 Therefore, in order to get a better representation of the bulk, the batches were sieved. Accordingly, 10 g from each lot was placed on an Endecott™ sieve shaker (Minor 200) equipped with 1000 µm, 500 µm and 106 µm stainless steel woven wire sieves that were pre-weighed. The shaker was operated for a total of 10 min after which time the sieves were removed, weighed and the percent retained above the 1000 µm and between the 500 and 1000 µm sieves was plotted (Figure 4). Interestingly, the batches with the lowest levels of agglomerates were those with the largest PSD (Lots B and E). 16 ACS Paragon Plus Environment

Page 17 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Examination under the microscope showed these batches to consist of individual thicker needles. The impact of particle size on the propensity of a compound to agglomerate during agitated drying has been studied extensively for this compound and has been previously reported.24 It has been found that larger particles tend to have a lower propensity to agglomerate rationalizing the observation with Lots B and E. Attempts to delump batches E – H using a hammer mill with a 0.75 mm screen, in order to avoid any potential DP manufacturability issues, were unsuccessful, with the material failing to flow through the mill (average Carr Index = 51.2). As a result, feeder screws were used to delump any large agglomerates and the batches were manually sieved using a 1 mm screen. While slightly improved results were obtained during the full scale delumping, possibly due to the ability to apply greater forces than the sieve shaker, a similar trend was observed (Figure 4). Clearly an improved crystallization process that affords larger, thicker individual particles was required to afford better control through the isolation process and to eliminate the formation of agglomerates. Development of a 2nd Generation TAK-117/DMSO Process Impact of seed. While primary nucleation appeared to be consistent on the lab scale, variation at plant scale may have impacted the PSD. This could have been attributed to either differences in mixing, the presence of varying impurities from the crude API or slight variations in the solvent composition resulting from variation in the DMSO hold-up during the filtration of the large amounts of carbon, celite and scavenger.25-27 It was anticipated that nucleation could be controlled by the implementation of a seeding step. Due to stability concerns with prolonged aging of the API in the presence of water at elevated temperatures, sufficient supersaturation for seeding (~10 %) was generated by cooling a saturated solution of TAK-117 in DMSO from 100 °C to 90 °C. In the absence of seed, TAK-117 was found to have very long induction times (240 min at S = 3.8, T = 21 °C; 79 min at S = 5.1, T = 21 °C) indicating very slow nucleation kinetics. Two different seed types of varied PSD were investigated, a micronized lot (d10= 0.7 µm, d50 = 3.6 µm, d90 = 7.7 µm) and material from batch B which consisted of non-agglomerated crystals of a larger PSD (d10= 6.6 µm, d50 = 21.8 µm, 17 ACS Paragon Plus Environment


Page 18 of 28

d90 = 110.9 µm). For all experiments conducted, the seed was added as a slurry in DMSO and the resulting suspension was aged for 30 min to allow for its maturation, before cooling to 25 °C at 10.8 °C/h. Water (3 vol.) was then added over 3 h to maximize recovery. Based on the solubility data shown in Figure 3, approximately 85 % of the batch was crystallized during the cooling portion of the crystallization, minimizing the impact of the antisolvent which was significantly greater when added at higher temperatures. It was desired to rely as much as possible on cooling, as opposed to antisolvent, for product recovery as cooling crystallizations are inherently more robust to scale-up, since mixing effectiveness is not as critical and temperature can be controlled better than antisolvent incorporation into the bulk. As expected, even at the relatively high seed loading of 5 wt%, the larger PSD seed resulted in buildup of supersaturation followed by its rapid release at 60 °C (Figure 5). Good desupersaturation rates were observed with all investigated loadings (0.5 wt%, 1.0 wt% and 5.0 wt%) of micronized seed with some clear differences observed at the higher temperatures (Figure 5). At 0.5 wt% loading there was not sufficient surface area for growth at the investigated cooling rate, resulting in some build-up of supersaturation and possibly some secondary nucleation between 80 and 70 °C. This is less pronounced with the 1.0 wt% seed which was ultimately selected for further optimization, offering a good balance between PSD and control of supersaturation.


Page 19 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 5. Effect of seed loading and particle size on the rate of desupersaturation for the 2nd generation DMSO process. Impact of thermalcycling. The crystals obtained from the revised seeded process were still long and thin, and thermalcycling was investigated in an attempt to further improve the particle size and morphology of TAK-117. This technique is used to enhance the PSD through successive heat and cool cycles that promote dissolution of the finer particles and growth of the coarser size range by redistribution of the solute resource occupied by the fine particles.15, 17

Figure 6. Optical microscope images of isolated TAK-117 at 40x magnification: A) no thermalcycling, B) 3 thermalcycles between 50 and 70 °C, C) 16 thermalcycles between 50 and 70 °C, D) 1 thermalcycle between 60 and 80 °C, and E) 3 thermalcycles between 60 and 80 °C. F) shows a scanning electron microscopy (SEM) image of 6E. Approximately 30 % of the crystal mass was thermalcycled at two different temperature ranges (50 – 70 °C and 60 – 80 °C). The decision to cycle almost one third of the crystal mass was based on analysis of the output size distribution from the 1st generation TAK-117/DMSO process, which highlighted approximately 30 % of the mass to be comprised of undesirable particles ≤5 µm. In the design of such processes, which may rely on numerous cycles, it is critical to select appropriate heating and cooling rates that balance provision of sufficient time to allow for finer particle 19 ACS Paragon Plus Environment


Page 20 of 28

dissolution and promotion of crystal growth, in lieu of secondary nucleation, while also maintaining acceptable manufacturing cycle times. With this in mind, relatively fast thermalcycle heating and cooling rates of 20 and 10 °C/h respectively were investigated, resulting in a 3 h cycle time that was an acceptable time extension to the process. In general, TAK-117 showed a tendency to exhibit aggregation, which manifested as quite significant cementing of crystals that was amplified and became more apparent as a result of repetitive heat and cool cycles (Figures 6A ‒ C). In the example shown without thermalcycling (Figure 6A), different degrees of aggregation are seen; from crystal structures that look loosely bound together, to those where the crystals appear fused together. By applying thermalcycling, the latter type of aggregation appears to become more prevalent and the bulk width of the crystal morphology increases due in most part to cementing of individual crystals rather than significant increases in the particle size of the discrete crystal. While the exact mechanism for this is not known, it is hypothesised that upon heating, the crystal dissolution process may promote formation of sites that develop crystalline bridges to develop between adjoining crystals during the cool down. Thermalcycling at elevated temperatures produced longer more defined aggregates (Figures 6B and 6E) and improved the aspect ratio from 0.15 to 0.21. It was found that impurities and residual solvent were not entrained in the aggregates, and material of acceptable quality was obtained that was sufficiently large as to not pose any risk of subsequent agglomeration during drying. Therefore, while the morphology was far from ideal, thermalcycling was incorporated into the process.


Page 21 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 7. Impact of seed on particle size and morphology. Optical microscope images of isolated TAK-117 at 40x magnification: A) using material from typical thermalcycled process as seed, B) using material from 7A as seed, C) using material from 7B as seed; D) from wet-milling of nonseeded process at 60 °C for 2 h followed by thermalcycling, E) from wet-milling of seeded process at 90 °C for 2 h followed by thermalcycling, and F) from wet-milling of seeded process at 60 °C for 2 h followed by thermalcycling. Attempts to utilize the product of each successive batch as seed for the next failed, with material of progressively smaller PSD being formed, even when a relatively high seed loading of 5 wt% was used (Figure 7A-C). As it was not desirable to have to micronize TAK-117 solely for generation of seed as well as to manage the supply chain of an additional raw material, wet-milling of the seed bed was investigated as a means of normalizing its PSD. Wet-milling of an unseeded process at 60 °C for 2 h using an IKA® T10 disperser with an S10N-10G probe at 30,000 rpm, followed by thermalcycling afforded material that was significantly more aggregated and of a smaller particle size with a large number of fine particles (Figure 7D vs. 6F). An improved morphology, comparable to that of the process seeded with micronized material, was obtained when the seed bed was wet-milled at 90 °C for 2 h (Figures 7E vs. 6F). The aspect ratio was greatly improved when the process was wet-milled at 60 °C for 2 h post-seeding at 90 °C with typical material obtained from the optimized 2nd generation 21 ACS Paragon Plus Environment


Page 22 of 28

TAK117/DMSO process (seed shown in Figure 6F, product in Figure 7F). This was presumably due to the generation of a larger population of crystals of a tighter PSD through milling, followed by dissolution of the resulting fines, the mass of which was then redistributed to the larger particles. Clean, dry, nitrogen flushed reactor

Charge water (3 L/ kg) over 6 hrs

TAK-117, crude DMSO (33 L/ kg)

Age for NLT 1 hr Heat to 100 ± 5 °C until full dissolution Isolate solids via filtration

Cool to 90 ± 5 °C at 1 °C/ min

Filtrate

DMSO:Water/ 10:1 (4 L/ kg) TAK-117, seed (1 wt%) in DMSO (0.27 L/ kg)

Organic wash

Water (4L/ kg)

Cool to 60 ± 5 °C at 0.2 °C/ min & hold for NMT 30 min

Reslurry solids for 1 h

Heat to 80 ± 5 °C at 0.2 °C/ min & hold for NMT 30 min

Isolate solids via filtration Filtrate

2 x Water (4 L/ kg) Thermalcycling


Aqueous wash 2 x Ethanol (4 L/ kg)

Heat to 80 ± 5 °C at 0.2 °C/ min & hold for NMT 30 min


Organic wash

Dry under vacuum at 50 °C

TAK-117

Figure 8. Overview of optimized 2nd generation DMSO TAK-117 crystallization process. Scale-up studies. Unfortunately the pilot plant used for the manufacture of TAK-117 was not equipped with a suitable wet-mill for the intended operating scale, and therefore micronized seed was used. Accordingly, crude TAK-117 was charged to a 1,000 L stainless steel reactor followed by activated carbon, Celite®, a suitable scavenger and DMSO. The suspension was heated to 100 ± 5 °C for 3 ‒ 4 h to remove any residual Pd and was filtered into a clean reactor. The solution was cooled to 90 ± 5 °C, was seeded with a suspension of micronized TAK-117 dispersed in DMSO and was aged at this temperature for approximately 1 h (Figure 8). The resulting suspension was cooled to 60 ± 5 °C over 1.5 h and was thermalcycled to 80 ± 5 °C before being cooled down to 25 ± 5 °C. Water was


Page 23 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


finally charged over 6 h and the resulting slurry was isolated and was dried to afford TAK-117 in excellent yield (88 ‒ 93 %) and LCAP purity (>99.6 %) with

Development and Scale-Up of a Crystallization ... - ACS Publications

Recommend Documents